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Clinical Endocrinology of Pregnant Mares
Published in Juan Carlos Gardón, Katy Satué, Biotechnologies Applied to Animal Reproduction, 2020
Recently, Wynn et al. (2018b) compared P4, 5α-DHP, allopregnanolone, 3β5P, 20α5P, βα-diol, and ββ-diol concentrations in plasma of mares with experimentally induced, ascending placentitis compared with gestationally age-matched control mares. In mares with chronic placentitis, concentrations of DHP and its metabolites (allopregnanolone, 3β5P, 20α5P, βα-diol) increased at 2–8 days prior to abortion compared with control mares. Of these pregnanes, 20α5P and βα-diol increased at 8 days prior to abortion and demonstrated the largest increase (3–4 times) in mares with chronic placentitis compared with control mares. P4 concentrations were at or below the limit of detection (0.5 ng/mL) for control mares and were increased at two days prior to abortion in mares with chronic placentitis but were not different from controls in mares with acute placentitis. In mares with acute placentitis, concentrations of DHP, allopregnanolone, 3β5P, 20α5P, and βα-diol decreased within 0–3 days prior to abortion. In mares with chronic placentitis, the patterns of increased pregnanes metabolized by the placenta were similar to changes in normal mares beyond day 300 of gestation and likely represent the effects of fetal stress and adrenal activation on pregnane metabolism by the fetus and placenta. Decreases in these same pregnanes in mares with acute cases likely reflect extreme fetal or placental compromise. These studies were useful to understand how differential issues during the pregnancy could present as different pregnane profiles.
Phytoextracts and Their Derivatives Affecting Neurotransmission Relevant to Alzheimer’s Disease
Published in Akula Ramakrishna, Victoria V. Roshchina, Neurotransmitters in Plants, 2018
Pregnane-type steroidal alkaloids: Sarcococca hookeriana:Bioactive-guided fractionation of Sarcococca hookeriana (Family: Buxaceae) resulted in two new pregnane-type steriodal alkaloids hookerianamide H and hookerianamide I [Figure 21.3 (xi and xii)] along with three alkaloids viz. N-α-methyl-epipachysamine D, sarcovagine C and dictyophlebine. All compounds showed significant inhibitory activities against AChE and BChE with IC50 value ranging from 2.9 to 34.1 mM and 0.3–3.6 mM, respectively (Khalid et al., 2004).Salignenamides C, E, and F, Axillarine-C, Saligcinnamide, Vaganine-A, 5,6-dehydrosarconidine, 2-hydroxysalignarine-E, Salignamine, 2-hydroxysalignamine-E, Epipachysamine-D, Dictyophlebine, iso-N-formylchone-morphine, and Axillaridine-A isolated from Sarcococca saligna (Family: Buxaceae) inhibited both AChE and BChE non-competitively with IC50 value ranging from 2.65–250.0 µM against AChE and 1.63–30.0 µM against BChE (Jing et al., 1999)
Herbs with Antidepressant Effects
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
Hypericum perforatum appears to have multiple mechanisms of action in producing antidepressant effects. Hypericum perforatum, particularly hyperforin, inhibits neuronal uptake not only of serotonin and noradrenaline – the common mechanisms of action of standard antidepressant medications – but also of dopamine, gamma-aminobutyric acid, and l-glutamate. Moreover, hyperforin does not act as a competitive inhibitor at the transmitter binding sites of the transporter proteins, but rather it affects the sodium gradient that in turn leads to an inhibition of transmitter uptake.19 In a 2014 paper by Sell et al.,20 it was admitted that we still do not understand the mechanism of action of hyperforin, the primary antidepressant component of Hypericum perforatum. Among the possibilities noted were: inhibition of 5-lipoxygenase; high affinity binding to the pregnane X receptor; release of Ca2+ and/or Zn2+ from intracellular stores; as well as the prominent hypothesis of diminishing reuptake of serotonin, dopamine, norepinephrine, acetylcholine, GABA, and glutamate. An earlier study had purported to show that hyperforin reduces uptake of the variety of neurotransmitters through activation of the somewhat mysterious neuronal channel protein, TRPC6. The activation of TRPC6 by hyperforin was also said to induce neuronal axonal sprouting, such as would be seen after the addition of various nerve growth factors.21 However, Sell et al. found that the large hyperforin molecule might act as a protonophore independently of TRPC6, thereby altering local membrane electrical currents and affecting neurotransmitter uptake. In any case, the mechanism of action of Hypericum perforatum is clearly unusual, and its full elucidation may point the way to development of unique antidepressants.
Assessment of Herb-Drug Interaction Potential of Five Common Species of Licorice and Their Phytochemical Constituents
Published in Journal of Dietary Supplements, 2023
Mona H. Haron, Bharathi Avula, Zulfiqar Ali, Amar G. Chittiboyina, Ikhlas A. Khan, Jing Li, Vivian Wang, Charles Wu, Shabana I. Khan
Studies have shown that the effect of drugs on CYP3A4 may be related to activation of human Pregnane X receptor (hPXR) (42–44), which is consistent with our results. To support further on a molecular level, several key ligand-protein, including hydrogen-bonding interactions, were observed between PXR and glabridin/glycycoumarin with the computational mining approach (unpublished data). Nevertheless, for further confirmation of possible effects of licorice extracts and their constituents on drug metabolism, we investigated if an increase in CYP3A4 enzymatic activity, caused by G. glabra, G. uralensis, G. inflata, and two of their most abundant constituents, glabridin, and glycycoumarin, could enhance the metabolism of drugs that are substrates of CYP3A4. For this purpose, we selected two of the most commonly prescribed antiretroviral drugs, dolutegravir and rilpivirine. Our data showed an enhanced metabolism of both drugs in hepatocytes treated with G. glabra and G. uralensis extracts. However, out of the two pure compounds tested, only glycycoumarin caused a considerable increase in drug metabolism. The overall ineffectiveness of glabridin on the metabolism of these drugs could be due to its inhibitory effect on CYP3A4 (12) and the lack of significant induction of CYP3A4 despite strong activation of PXR as observed in the current study.
Effect of 3α-dihydroprogesterone and 5α-dihydroprogesterone on DCIS cells and possible impact for postmenopausal women
Published in Climacteric, 2023
M. Sourouni, M. Götte, L. Kiesel, M.-K. von Wahlde
Available commercial kits measure only progesterone and do not measure relevant major metabolites which may also play a role in the carcinogenic process. A number of progesterone metabolites have been characterized and broadly fall into two groups: 4-pregnenes, metabolites that retain their double bond; and 5α-pregnanes, metabolites in which 5α-reductase has reduced the double bond [3]. Different relative distributions in the 4-pregnenes and 5α-pregnanes have been demonstrated in normal and cancerous breast tissue. Conversion to 4-pregenene metabolites predominates in normal breast tissue, while conversion to 5α-pregnane predominates in breast cancer. Therefore, it is suggested that changes in the concentrations of cancer-inhibiting 4-pregnenes (e.g. 3αP) and cancer-promoting 5α-pregnanes (e.g. 5αP) may be related to the promotion of breast cancer [32].
Effect of inflammation on cytochrome P450-mediated arachidonic acid metabolism and the consequences on cardiac hypertrophy
Published in Drug Metabolism Reviews, 2023
Mohammed A. W. ElKhatib, Fadumo Ahmed Isse, Ayman O. S. El-Kadi
Several transcription-dependent mechanisms are involved in inflammation-mediated reduction in CYPs activity based upon inflammatory stimuli type, response time point, and specific CYP gene. For the majority of CYPs investigated, a pre-translation mechanism, encompassing reduced levels of CYP mRNA with consequent reduction in CYP proteins, contributes to the inflammatory impact observed for the alterations in CYPs expression. Clearly, NF-κB plays a pivotal role in CYP regulation through interacting with their signaling pathways (Aitken et al. 2006; Morgan 2009). For instance, inflammation-induced suppression of CYP1A2 and CYP1A2 transcription is attributed to mutual antagonistic interaction of NF-κB with aryl hydrocarbon receptor (AhR) through binding of NF-κB to AhR and subsequent functional suppression of both of them (Ke et al. 2001). Other proposed mechanisms for inflammation-mediated CYP downregulation include NF-κB interaction with constitutive androstane receptor (CAR) and pregnane X receptor (PXR) (Beigneux et al. 2002; Kim MS et al. 2003; Aitken et al. 2006; Morgan 2009). Although pretranscriptional repression is the major factor in the downregulation of CYPs by inflammation, multiple post-transcription mechanisms are also implicated in this phenomenon, for example, inflammation-induced NO production via inducible NO synthase (iNOS) which downregulates CYP2B6 and CYP2B1 (Aitken et al. 2008; Lee et al. 2008).